Project Summary Epigenetics refers to functional modifications to the genome that do not involve a change in the DNA sequence. Epigenetics became an attractive field in recent years within the drug discovery research communities. Key enzymes in epigenetic regulation - the histone deacetylases (HDACs) - may be a promising epigenetic target for the development of new therapeutics. HDAC enzymes modulate gene expression, influencing an array of cellular operations, all of which are critical components in the pathophysiology of a number of diseases. HDACs have been implicated in a wide-range of central nervous system (CNS) disorders and may offer new therapeutic opportunities. Among HDAC isoforms, HDAC6 is a unique enzyme and preclinical studies provide robust evidence for the involvement of HDAC6 in various neurological diseases. However, existing HDAC6-selective inhibitors do not penetrate the blood-brain barrier. In this grant application, our proposed work is a multi-disciplinary project and the first to use preclinical, in vivo neuroimaging with the translational PET probe for HDAC6, termed [18F]Bavarostat, developed from our lab to assist the development of novel HDAC6-selective inhibitors with high brain exposure. This tool provides a new way to visualize epigenetics in the brain and it will be accelerate the discovery of new HDAC6 inhibitors for brain disorder treatment.